1 Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
Mol Pain. 2018 Jan-Dec;14:1744806918778490. doi: 10.1177/1744806918778490.
Emerging evidence showed that hyperpolarization-activated cation channels (HCN) participate in the development of inflammatory and neuropathic pain. However, the role of HCN2 in oxaliplatin-induced neuropathic pain remains unknown. Here, we found that HCN2 expression was upregulated in a rat model of oxaliplatin-induced neuropathic pain. Intrathecal injection of ZD7288, an HCN specific inhibitor, decreased the HCN2 level, as well as weakened the neuropathic pain behaviors compared to naive rats. Besides, mechanistic studies revealed that the expression of the spinal N-methyl-D-aspartate receptor subunit 2B was increased after oxaliplatin administration and was reduced by ZD7288 administration. The nociceptive behaviors were reversed by NR2B antagonist Ro 25-6981 in HCN2-overexpression rats. Furthermore, the underlying cellular mechanism demonstrated that ZD7288 administration restrained the enhanced activation of the neuronal calcium-calmodulin-dependent kinase II (CaMKII)/cyclic adenosine monophosphate response element-binding protein cascade after oxaliplatin administration. Moreover, pretreatment of CaMKII inhibitor KN-93 suppressed the nociceptive behaviors, as well as NR2B upregulation induced by overexpression of HCN2. In a word, HCN2 is conducive to oxaliplatin-induced neuropathic pain by activating the neuronal CaMKII/CREB cascade.
新出现的证据表明，超极化激活阳离子通道（HCN）参与了炎症性和神经性疼痛的发展。然而，HCN2 在奥沙利铂诱导的神经性疼痛中的作用尚不清楚。在这里，我们发现 HCN2 的表达在奥沙利铂诱导的神经性疼痛大鼠模型中上调。鞘内注射 HCN 特异性抑制剂 ZD7288 可降低 HCN2 水平，并减弱神经病理性疼痛行为，与未处理的大鼠相比。此外，机制研究表明，奥沙利铂给药后脊髓 N-甲基-D-天冬氨酸受体亚单位 2B 的表达增加，ZD7288 给药后减少。在 HCN2 过表达大鼠中，NR2B 拮抗剂 Ro 25-6981 逆转了伤害性行为。此外，潜在的细胞机制表明，ZD7288 给药抑制了奥沙利铂给药后神经元钙调蛋白依赖性激酶 II（CaMKII）/环磷酸腺苷反应元件结合蛋白级联的增强激活。此外，CaMKII 抑制剂 KN-93 的预处理抑制了由 HCN2 过表达引起的伤害性行为以及 NR2B 的上调。总之，HCN2 通过激活神经元 CaMKII/CREB 级联促进奥沙利铂诱导的神经性疼痛。
